Most inflammatory kidney diseases have the final outcome of fibrosis with the loss of kidney architecture and progressive loss of kidney function. Excess matrix deposition is observed, which may be an inadequate attempt to limit organ damage. The primary sources of matrix synthesis are resident cells that may acquire different activated phenotypes and likely orchestrate matrix deposition. Over the last decades, intense efforts were undertaken to define the origin of myofibroblasts, resulting in four different controversially discussed hypotheses: bone marrow recruitment, vascular pericyte-derived myofibroblasts, epithelial-to-mesenchymal transition (EMT), and endothelial-to-mesenchymal transition (EndMT). In a recent article, LeBleu et al. (Nat Med 19(8):1047-1053, 2013) address this issue and come to the conclusion that most of the different hypotheses are likely true, however to different extents. To arrive at this conclusion, the authors have performed genetic cell tracking and quantification by cell labeling in newly generated knockout mouse models. Quantitative analyses have been made and yield the following estimates: 50% of the myofibroblasts are derived through proliferation from resident fibroblasts, 35% differentiate from bone marrow-derived cells, 10% arise from EndMT, and 5% through EMT.
